Molecular Mechanism of Hypothalamus Development in Zebrafish

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Abstract

The hypothalamus is a key integrative center in the brain consisting of diverse cell types that differ in morphology and the neuropeptides they produce. These neuropeptides
are required for the pivotal functions of the hypothalamus including homeostasis, reproduction, cognitive behavior and stress response. Despite the knowledge of several transcription factors important for the hypothalamic neuronal development, little is known about how these transcription factors act in concert to generate the amazing
diversity of neuron types present in the hypothalamus. In this study, I focus on the development of two hypothalamic areas in zebrafish, the preoptic area and the posterior
hypothalamus. The preoptic area plays an important role in homeostasis and stress response whereas the posterior hypothalamus is important for cognitive behavior in
mammals. Consistent with their different functions, these two areas are composed of distinct neuron types. However, the mechanism that contributes to this difference remains
largely unknown. In this thesis, I characterize the roles of four transcription factors, Fezf2, Otp, Sim1a and Foxb1.2, for the development of the preoptic area and posterior hypothalamus. I show that early in development Fezf2 is important for the regionalization of the posterior hypothalamus, while later Fezf2 interacts with Otp, Sim1a and Foxb1.2 to specify distinct neuron types. Interestingly, these regulatory interactions change during
development and vary between the anterior and the posterior hypothalamus, contributing to the formation of regional differences in these areas. Further, these interactions generate different domains in the posterior hypothalamus and contribute to the specification of distinct neuron types such as those that produce vasoactive intestinal peptide (VIP) and urotensin 1 (Uts1). In summary, this study provides the first regulatory and molecular map of the posterior hypothalamus and demonstrates that the specification of preoptic and posterior hypothalamic neurons require the dynamic regulatory interactions of Fezf2
together with Otp, Sim1a and Foxb1.2.